ClinVar Genomic variation as it relates to human health
NM_000053.4(ATP7B):c.3649_3654del (p.Val1217_Leu1218del)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000053.4(ATP7B):c.3649_3654del (p.Val1217_Leu1218del)
Variation ID: 189015 Accession: VCV000189015.40
- Type and length
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Deletion, 6 bp
- Location
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Cytogenetic: 13q14.3 13: 51939096-51939101 (GRCh38) [ NCBI UCSC ] 13: 52513232-52513237 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 29, 2015 Apr 20, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000053.4:c.3649_3654del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000044.2:p.Val1217_Leu1218del inframe deletion NM_000053.3:c.3649_3654del NM_001005918.3:c.3028_3033del NP_001005918.1:p.Val1010_Leu1011del inframe deletion NM_001243182.2:c.3316_3321del NP_001230111.1:p.Val1106_Leu1107del inframe deletion NM_001330578.2:c.3415_3420del NP_001317507.1:p.Val1139_Leu1140del inframe deletion NM_001330579.2:c.3397_3402del NP_001317508.1:p.Val1133_Leu1134del inframe deletion NC_000013.11:g.51939098_51939103del NC_000013.10:g.52513234_52513239del NG_008806.1:g.77394_77399del - Protein change
- Other names
- p.Val1217_Leu1218del
- Canonical SPDI
- NC_000013.11:51939095:CAGAACCA:CA
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ATP7B | - | - |
GRCh38 GRCh37 |
2850 | 2991 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Nov 30, 2023 | RCV000169402.20 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV001091635.17 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jan 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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Wilson disease
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001160221.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The ATP7B c.3649_3654delGTTCTG; p.Val1217_Leu1218del variant (rs781266802) also known as 3648del6, is reported in the literature in the compound heterozygous state in multiple individuals affected with … (more)
The ATP7B c.3649_3654delGTTCTG; p.Val1217_Leu1218del variant (rs781266802) also known as 3648del6, is reported in the literature in the compound heterozygous state in multiple individuals affected with Wilson's disease (Ferenci 2005, Folhoffer 2007, Kalinsky 1998, Kemppainen 1997, Loudianos 1998, Petrasek 2007, Thomas 1995, Todorov 2005, Vrabelova 2005, Wright 2009). This variant deletes two amino acid residues leaving the rest of the protein in-frame. This variant is reported in ClinVar (Variation ID: 189015), and is found in the Finnish European population with an allele frequency of 0.014% (3/21,562 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. References: Ferenci P et al. Diagnostic value of quantitative hepatic copper determination in patients with Wilson's Disease. Clin Gastroenterol Hepatol. 2005 Aug;3(8):811-8. Folhoffer A et al. Novel mutations of the ATP7B gene among 109 Hungarian patients with Wilson's disease. Eur J Gastroenterol Hepatol. 2007 Feb;19(2):105-11. Kalinsky H et al. Novel ATP7B mutations causing Wilson disease in several Israeli ethnic groups. Hum Mutat. 1998;11(2):145-51. Kemppainen R et al. A homozygous nonsense mutation and a combination of two mutations of the Wilson disease gene in patients with different lysyl oxidase activities in cultured fibroblasts. J Invest Dermatol. 1997 Jan;108(1):35-9. Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998;12(2):89-94. Petrasek J et al. Revised King's College score for liver transplantation in adult patients with Wilson's disease. Liver Transpl. 2007 Jan;13(1):55-61. Thomas GR et al. The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet. 1995 Feb;9(2):210-7. Todorov T et al. Spectrum of mutations in the Wilson disease gene (ATP7B) in the Bulgarian population. Clin Genet. 2005 Nov;68(5):474-6. Vrabelova S et al. Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. Mol Genet Metab. 2005 Sep-Oct;86(1-2):277-85. Wright LM et al. Hepatocyte GP73 expression in Wilson disease. J Hepatol. 2009 Sep;51(3):557-64. (less)
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Pathogenic
(Aug 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Wilson disease
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001977243.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Likely pathogenic
(Oct 15, 2014)
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criteria provided, single submitter
Method: literature only
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Wilson's disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220801.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Jul 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Wilson disease
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004216372.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Aug 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Wilson disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001221643.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189015). This variant is also known … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189015). This variant is also known as 3648del6. This variant has been observed in individual(s) with Wilson disease (PMID: 8980283, 9482578, 17154398, 17272994, 19118915). This variant is present in population databases (rs781266802, gnomAD 0.02%). This variant, c.3649_3654del, results in the deletion of 2 amino acid(s) of the ATP7B protein (p.Val1217_Leu1218del), but otherwise preserves the integrity of the reading frame. (less)
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247792.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Comment:
ATP7B: PM3:Strong, PM1, PM2, PM4
Number of individuals with the variant: 2
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Pathogenic
(Mar 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226647.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP4, PM2, PM3_strong, PM4, PS4_moderate
Number of individuals with the variant: 1
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Likely Pathogenic
(Nov 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Wilson disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004845317.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This variant causes an in-frame deletion of two amino acids (p.Val1217_Leu1218del) in exon 17 of the ATP7B protein. This variant is also known as 3648del6 … (more)
This variant causes an in-frame deletion of two amino acids (p.Val1217_Leu1218del) in exon 17 of the ATP7B protein. This variant is also known as 3648del6 in the literature. Although functional studies have not been reported, this variant disrupts two conserved amino acids in the Phosphorylation (P) domain (a.a. 1004-1031, 1197-1312) of the ATP7B protein that is involved in the ATP hydrolysis, a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). This variant has been reported in over 15 individuals affected with Wilson disease (PMID: 7626145, 8980283, 9482578, 16207219, 16234011, 17154398, 17272994, 19118915, 19596473, 20082719, 22677543, 25014046, 31708252, 34400371). In several of these individuals, this variant was reported in the compound heterozygous state and homozygous state (PMID: 9482578, 17272994, 19118915). This variant has been identified in 9/249600 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Number of individuals with the variant: 5
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Structure of the Wilson disease copper transporter ATP7B. | Bitter RM | Science advances | 2022 | PMID: 35245129 |
ATP7B variant spectrum in a French pediatric Wilson disease cohort. | Couchonnal E | European journal of medical genetics | 2021 | PMID: 34400371 |
The spectrum of pathogenic variants of the ATP7B gene in Wilson disease in the Russian Federation. | Balashova MS | Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) | 2020 | PMID: 31708252 |
Liver cirrhosis in patients newly diagnosed with neurological phenotype of Wilson's disease. | Przybyłkowski A | Functional neurology | 2014 | PMID: 25014046 |
Molecular analysis of Wilson patients: direct sequencing and MLPA analysis in the ATP7B gene and Atox1 and COMMD1 gene analysis. | Bost M | Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) | 2012 | PMID: 22677543 |
Truncating mutations in the Wilson disease gene ATP7B are associated with very low serum ceruloplasmin oxidase activity and an early onset of Wilson disease. | Merle U | BMC gastroenterology | 2010 | PMID: 20082719 |
Hepatocyte GP73 expression in Wilson disease. | Wright LM | Journal of hepatology | 2009 | PMID: 19596473 |
Genotype-phenotype correlation in Italian children with Wilson's disease. | Nicastro E | Journal of hepatology | 2009 | PMID: 19118915 |
Novel mutations of the ATP7B gene among 109 Hungarian patients with Wilson's disease. | Folhoffer A | European journal of gastroenterology & hepatology | 2007 | PMID: 17272994 |
Revised King's College score for liver transplantation in adult patients with Wilson's disease. | Petrasek J | Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society | 2007 | PMID: 17154398 |
Diagnostic value of quantitative hepatic copper determination in patients with Wilson's Disease. | Ferenci P | Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association | 2005 | PMID: 16234011 |
Spectrum of mutations in the Wilson disease gene (ATP7B) in the Bulgarian population. | Todorov T | Clinical genetics | 2005 | PMID: 16207219 |
Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. | Loudianos G | Human mutation | 1998 | PMID: 9671269 |
Novel ATP7B mutations causing Wilson disease in several Israeli ethnic groups. | Kalinsky H | Human mutation | 1998 | PMID: 9482578 |
A homozygous nonsense mutation and a combination of two mutations of the Wilson disease gene in patients with different lysyl oxidase activities in cultured fibroblasts. | Kemppainen R | The Journal of investigative dermatology | 1997 | PMID: 8980283 |
The Wilson disease gene: spectrum of mutations and their consequences. | Thomas GR | Nature genetics | 1995 | PMID: 7626145 |
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Text-mined citations for rs781266802 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.